V i r a l Pn e u m o n i a an d

A c u t e Re s p i r a t o r y
D i s t res s S y n d rom e
Raj D. Shah, MD, Richard G. Wunderink, MD*

KEYWORDS
 Acute respiratory distress syndrome  Respiratory virus  Community-acquired pneumonia

KEY POINTS
 Respiratory viruses are increasingly recognized in patients with severe community-acquired pneu-
monia and acute respiratory distress syndrome (ARDS).
 Pandemic and seasonal respiratory viral infections have been implicated in the pathogenesis of
ARDS in adults.
 Supportive care for adults with ARDS caused by respiratory viruses is similar to the care of patients
with ARDS from other causes.
 Antiviral therapy is available for some respiratory viral infections; however, further research is
needed to determine which groups of patients would benefit.

INTRODUCTION (RT-PCR) assays, have increased recognition

Acute respiratory distress syndrome (ARDS) is a
severe form of inflammatory lung injury character-
ized by increased vascular permeability in the
lung.1 Clinically, ARDS is defined by the presence
of severe hypoxemia and bilateral opacities on
chest imaging that are not explained by the pres-
ence of cardiac failure or volume overload.2,3
Community-acquired pneumonia (CAP) is the
most common cause of ARDS that develops
outside of the hospital.4 Respiratory viruses are
increasingly recognized in patients with severe
CAP and ARDS.5,6 This article reviews the epide-
miology, diagnosis, and management of adult pa-
tients with severe pneumonia and ARDS caused
by viral respiratory pathogens.
EPIDEMIOLOGY
Improved diagnostic testing, particularly multiplex
reverse transcription polymerase chain reaction
that respiratory viruses cause critical illness in
adults.7–9 Although no studies have reported the
incidence of ARDS specifically caused by viral
pneumonia, epidemiologic surveys of adults
admitted to the intensive care unit (ICU) with
pneumonia and respiratory failure suggest that
respiratory viruses are a common cause of severe
pneumonia.10,11 In the Etiology of Pneumonia in
the Community (EPIC) study, a population-based
surveillance for CAP, respiratory viruses were
identified in 22% of adults admitted to the ICU
with radiographically proven pneumonia.12 In a
prospective, observational study of consecutive
patients admitted to an ICU with CAP in 6 hospi-
tals in Kentucky, respiratory viruses were identi-
fied in 23% of adults.13 In a retrospective study
of 198 patients with pneumonia admitted to a sin-
gle ICU in South Korea, 36.4% had evidence of
viral pneumonia, including 23 patients with a virus
identified in bronchoalveolar lavage (BAL).5 In
chestmed.theclinics.com

Disclosure: None.
Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 676
North St. Clair Street, Arkes 14-045, Chicago, IL 60611, USA
* Corresponding author.
E-mail address: r-wunderink@northwestern.edu

Clin Chest Med - (2016) -–-

http://dx.doi.org/10.1016/j.ccm.2016.11.013
0272-5231/16/Ó 2016 Elsevier Inc. All rights reserved.
2 Shah & Wunderink
these series, influenza virus and rhinovirus were
the most commonly detected respiratory viruses,
identified in approximately 6% and 8% of cases
of viral pneumonia respectively. The prevalence
of identified bacterial coinfection was low, and
in 1 series5 the mortalities related to bacterial
and viral pneumonia were comparable.
Epidemiologic studies have shown that respi-
ratory viruses are an underappreciated cause of
severe CAP. However, the results of these
studies should be interpreted with caution for
several reasons. First, the viruses most
commonly detected in patients with CAP vary
across reports, which likely reflects differences
in patient populations, season, and geographic
location. Although respiratory viruses are
commonly detected in critically ill patients using
RT-PCR, their role in the pathogenesis of severe
pneumonia and ARDS is less clear.14,15 Respira-
tory viruses may be the sole cause of CAP and
ARDS in some patients, or may be a risk factor
predisposing patients to infections with other or-
ganisms, or may also represent concurrent upper
respiratory tract infection, colonization, or pro-
longed viral shedding.16–20
PATHOGENESIS
The pathogenesis of ARDS in patients infected
with respiratory viruses is incompletely under-
stood. Most adults with respiratory viral infec-
tions have mild symptoms. However, viral
strains associated with ARDS, such as the 2009
pandemic influenza A virus strain, are the iden-
tical to those seen in mild cases.21,22 A combina-
tion of variable host factors and the host immune
response therefore likely leads to the develop-
ment of severe pneumonia and ARDS. Detailed
review of the pathologic mechanisms implicated
in the development of ARDS caused by respira-
tory viruses is beyond the scope of this article,
but several excellent reviews on this topic
exist.23–26 Respiratory viruses initially infect the
nasal and bronchial epithelium. This point of en-
try leads to respiratory airway and alveolar endo-
thelial injury, elaboration of cytokines and
chemokines, and recruitment of both innate and
adaptive immune cells.27 Specific cytokine pro-
files vary by virus, but converge on a common
end pathway, resulting in the pathologic hallmark
of ARDS, diffuse alveolar damage.28–30 The
mechanisms of acute lung injury caused by viral
pathogens have important clinical implications;
if ARDS results from the inflammatory host
response rather than viral-mediated injury, then
antiviral therapy alone may not be central to res-
olution of lung injury.31
GENERAL APPROACH TO VIRAL PNEUMONIA
AND ACUTE RESPIRATORY DISTRESS
SYNDROME
Diagnosis
The diagnosis of ARDS should be considered in all
patients with respiratory viral infection, hypox-
emia, and bilateral opacities on chest radiography
unless there is strong clinical suspicion for cardio-
genic pulmonary edema or volume overload.
Criteria for diagnosing ARDS, referred to as the
Berlin criteria,2 are listed in Box 1. In resource-
limited settings, diagnostic testing to ensure that
patients meet each criterion, such as echocardi-
ography or arterial blood gas analysis, may not
be possible. In such situations, any patient with
hypoxemia and bilateral opacities on chest radiog-
raphy should be considered to have ARDS unless
strong clinical suspicion for cardiogenic pulmo-
nary edema or volume overload is present.32
Diagnosis of respiratory viruses can be made
using isolation of intact virus particles from cell cul-
ture, viral antigen detection by immunofluores-
cence, or multiplex RT-PCR. When available,
multiplex RT-PCR provides more rapid diagnosis
with equal or better sensitivity and specificity
compared with viral culture and immunofluores-
cence testing.33,34 Multiplex RT-PCR testing using
specimens collected from nasopharyngeal (NP)
Box 1
Definition of acute respiratory distress
syndrome, Berlin criteria
Within 1 week of known clinical insult or new
or worsening respiratory symptoms.
Bilateral opacities on chest imaging not fully ex-
plained by effusions, lobar/lung collapse, or
nodules.
Respiratory failure not explained by cardiac fail-
ure or fluid overload. Need objective assess-
ment such as echocardiography to exclude
hydrostatic edema if no risk factor present.
Impaired oxygenation:
Mild: 200< PaO2/FiO2 300 with PEEP or CPAP
5 cm H2O
Moderate: 100< PaO2/FiO2 200 with PEEP
5 cm H2O
Severe: PaO2/FiO2 100 with PEEP 5 cm H2O
Abbreviations: CPAP, continuous positive airway pres-
sure; FiO2, fraction of inspired oxygen; PEEP, positive
end-expiratory pressure.
Adapted from Force ADT, Ranieri VM, Rubenfeld
GD, et al. Acute respiratory distress syndrome: the Ber-
lin Definition. JAMA 2012;307:2526–33.

aspirate or BAL have higher sensitivity compared
with nasal swab.35 Studies comparing BAL and
NP aspirate have not shown one method to be su-
perior to the other.36 The optimal site of sampling
depends on the particular respiratory virus, incu-
bation time, and the duration of symptoms. For pa-
tients with viral pneumonia in whom bronchoscopy
can safely be performed, the combination of RT-
PCR testing from NP plus BAL specimens may in-
crease the diagnostic yield compared with NP
testing alone.37,38
Treatment
In additional antiviral therapy, special attention
should be paid to ventilator management and other
supportive care. Similar to ARDS of any other
cause, patients who require invasive mechanical
ventilation should be treated with a low-tidal-
volume strategy targeting 6 mL/kg of ideal body
weight.39–41 In cases of severe ARDS, consider-
ation should be given to salvage therapies,
including prone positioning and paralytic therapy
for the first 48 hours following intubation.42–44
Although noninvasive positive pressure ventilation
has been tried in patients with ARDS,45,46 reports
from the 2009 H1N1 pandemic suggest that this
strategy is not effective in patients with ARDS
caused by influenza.47 Patients with severe viral
infection are at risk for secondary bacterial pneu-
monia, because of both the effects of the virus
alone and the risk of ventilator-associated pneu-
monia from prolonged mechanical ventilation.48,49
Invasive tests, such as bronchoscopy, may be
helpful to differentiate bacterial coinfection from
viral pneumonia alone.5,50 In general, the empiric
use of antibiotic therapy in patients with viral pneu-
monia should be avoided and may increase the risk
of antibiotic resistance and subsequent nosoco-
mial infection.51,52 The use of intravenous cortico-
steroids in the treatment of ARDS has generally
not improved outcomes.53,54 In patients with
ARDS related to influenza and severe acute respi-
ratory syndrome (SARS), adjunctive corticoste-
roids have not improved outcomes and may
increase the risk subsequent nosocomial
infection.55,56
Extracorporeal membrane oxygenation (ECMO)
gained attention during the 2009 H1N1 influenza
pandemic after several studies reported low mor-
tality in patients with viral ARDS treated with this
modality.57,58 The only randomized clinical trial
that compared ARDS treatment with ECMO with
conventional care, the CESAR trial, enrolled a sig-
nificant proportion of patients with influenza.59
However, this trial had several significant method-
ological limitations; in particular, more patients in
Acute Respiratory Distress Syndrome 3
the ECMO arm were treated with a low-tidal-
volume ventilation strategy compared with pa-
tients in the conventional arm. In a retrospective
matched cohort study of patients with influenza
A (H1N1) and ARDS, the mortality in patients
treated with ECMO was similar to propensity
score–matched controls not treated with ECMO.60
PANDEMIC VIRUSES
Over the past 15 years, 3 respiratory viruses have
attracted special attention because of the high
proportion of affected patients who develop crit-
ical illness and ARDS: influenza, particularly influ-
enza A H1N1 2009; and 2 novel coronaviruses,
Middle Eastern respiratory syndrome coronavirus
(MERS-CoV) and SARS coronavirus (SARS-CoV).
Influenza Virus
Influenza A virus is the most frequently described
cause of viral pneumonia and ARDS in adult pa-
tients.26,61 Influenza A virus has a wide variety of
hosts and antigenic subtypes; this genetic diver-
sity allows the virus to cause annual epidemics,
as well as occasional pandemics. By contrast,
humans are the primary host for influenza B and
the virus relies mainly on genetic drift to propagate
epidemics.62
Influenza causes seasonal epidemics during the
winter months in the northern and south hemi-
spheres, and year-round in the tropics.63 Seasonal
influenza is a self-limited infection in the general
population, with an average annual mortality of
1.4 to 16.7 deaths per 100,000 persons. In the
United States, seasonal influenza accounts for an
estimated 18,491 to 95,390 ICU admissions
yearly.64 Adults greater than 65 years of age, resi-
dents of nursing homes and chronic care facilities,
pregnant women, patients with chronic medical
conditions, immune-compromised individuals,
and obese patients are at higher risk for more se-
vere disease and death.65,66
In 2009, a novel H1N1 strain of influenza A virus
was detected in the western United States and
Mexico, and quickly spread globally, triggering
the first influenza pandemic since 1968.67 The
new strain caused a range of clinical syndromes
in humans, ranging from mild self-limited illness
to fulminant pneumonia and ARDS.47,68,69 During
the 2009 pandemic in the United States, approxi-
mately 275,000 hospitalizations and in excess of
12,000 deaths were attributed to the 2009 H1N1
virus.70 ICU admission occurred in 9% to 31% of
hospitalized adults, and 14% to 47% of critically
ill adults died.71 Risk factors for poor outcomes
in hospitalized patients with H1N1 were age less
than 5 years, pregnancy (especially during the
4 Shah & Wunderink
third trimester), chronic medical illness, morbid
obesity, and immune suppression.72
In adults with influenza virus, the principal clin-
ical syndrome leading to ARDS is viral pneumonitis
and severe hypoxemic respiratory failure, some-
times accompanied by shock and acute renal fail-
ure.28,67 This syndrome accounted for most of the
ICU admissions during the 2009 pandemic.47,69,73
The radiographic presentation of influenza-
induced ARDS is similar to ARDS of any other
causes. On computed tomography scan of the
chest, influenza classically presents with bilateral
ground glass opacities, but areas of the alveolar
consolidation and air bronchograms are also com-
mon.74 Bacterial and viral coinfection is common,
particularly in patients greater than 65 years of
age, and can complicate up to 34% of cases.75
Radiographic findings typical of bacterial pneu-
monia, such as alveolar consolidation or air bron-
chograms, are not specific enough to confirm or
exclude the presence of secondary bacterial
pnuemonia.76 Other important complications of
influenza in critically ill patients include venous
thromboembolism, myocarditis, rhabdomyolysis,
and neurologic manifestations (confusion, sei-
zures, unconsciousness, encephalopathy, quadri-
paresis, and encephalitis).77,78
The neuraminidase inhibitors, oseltamivir and
zanamivir, are the mainstay of treatment of pa-
tients with influenza. Early administration of anti-
viral therapy may decrease progression to critical
illness in hospitalized patients.71
Typical dosing of oseltamivir is 75 mg twice
daily; however, optimal dosing and duration of
oseltamivir therapy in patients with ARDS is not
known. Treatment failure, as shown by persistent
influenza detection in BAL samples of critically ill
adults, was frequently reported during the H1N1
pandemic with standard-dose oseltamivir.67 Two
clinical trials comparing oseltamivir 75 mg twice
a day with 150 mg twice a day did not show any
significant difference in clinical outcomes, but the
proportion of critically ill subjects enrolled in each
trial was low.79,80 The authors recommend admin-
istration of a higher dose of oseltamivir of 150 mg
twice daily for up to 10 days for treatment of H1N1
or H5N1 influenza, and this dose should be
considered for patients with ARDS related to sea-
sonal influenza virus.
Zanamivir is available as an inhaled powder or
intravenous therapy.81 Zanamivir is generally well
tolerated but has not been extensively studied in
critically ill adults. The inhaled powder should be
avoided in patients with obstructive airways dis-
ease because it may provoke bronchospasm.
The use of nebulized zanamivir in mechanically
ventilated patients has been associated with
ventilator dysfunction caused by the lactose car-
rier.82 During the 2009 H1N1 pandemic, sporadic
reports of oseltamivir resistance were reported
caused by a mutation in viral neuraminidase; these
cases can be treated with intravenous zanamivir.83
Evidence for the use of adjuvant corticosteroid
therapy in patients with influenza infection and
ARDS is largely based on retrospective studies
form the H1N1 pandemic, and is conflicting.
Several studies have shown an increased risk of
nosocomial infection and mortality.55,84,85 Howev-
er, 1 study showed a reduction in the need for me-
chanical ventilation in patients with hematopoietic
stem cell transplant hospitalized with H1N1 influ-
enza.86 The authors recommend against the
routine use of corticosteroid therapy in patients
with influenza pneumonia and ARDS.
Middle Eastern respiratory syndrome
coronavirus
MERS-CoV is a novel lineage B coronavirus first
identified in Saudi Arabia in 2012.87,88 Since
then, sporadic cases and outbreaks have been re-
ported in people living in or recently traveling to the
Arabian Peninsula.89 MERS-CoV infects both
humans and camels via the CD26 receptor present
on nonciliated bronchial epithelial cells found in
the lower respiratory tract.90,91 Median incubation
time of the virus is 5 to 6 days, but can be as long
as 14 days.92 MERS-CoV should be suspected in
patients with an acute febrile respiratory illness
or CAP who live in or have recently traveled to
the Arabian Peninsula. Clinically, patients with
MERS-CoV can present with a range of symptoms
from mild upper respiratory symptoms to severe
pneumonia, acute renal failure, and ARDS.93
Gastrointestinal complaints, including diarrhea
and abdominal pain, are common and may pre-
cede the onset of respiratory symptoms.94 In one
case series of 47 hospitalized patients with
laboratory-confirmed cases of MERS-CoV, 42
(89%) needed intensive care and 34 (72%)
required mechanical ventilation.95 The reported
mortality in most case series exceeds 50%.95,96
Most hospitalized patients with MERS-CoV
have abnormal chest radiograph (CXR) or
computed tomography findings consistent with in-
fectious pneumonia, most commonly bilateral and
subpleural ground-glass opacities, although
lobular consolidation has also been described.97
In one series, microbiologic evidence from blood
and respiratory samples of bacterial, viral, or
fungal coinfection was not found in any patient,
suggesting that MERS-CoV was the sole organism
responsible for respiratory failure and ARDS.95
Diagnosis is made using RT-PCR obtained from

an NP, lower respiratory, or serum specimen.98 In
patients presenting with lower respiratory symp-
toms or severe illness, RT-PCR testing from a
lower respiratory source, such as sputum, endo-
tracheal aspirate, or BAL, is more sensitive than
testing from an upper respiratory source.99
Treatment of SARS-CoV is supportive, and to
date there are no prospective clinical trials of any
specific treatment intervention. Glucocorticoids
have been used as adjuvant therapy in patients
with severe MERS-CoV; however, there is no clear
evidence that this practice improves outcomes.100
Combination antiviral therapy with high-dose inter-
feron alfa-2b and ribavirin administered shortly af-
ter inoculation of MERS-CoV in rhesus macaques
showed a decrease in viral replication and radio-
graphic evidence of pneumonia. A retrospective
cohort study of 20 patients with MERS-CoV treated
with combination interferon alfa-2b and ribavirin
initiated a median of 3 days after diagnosis found
reduced 14-day mortality compared with 24 pa-
tients treated with supportive care alone.101 In
2015, a MERS-CoV antibody, LCA60, was isolated
from memory B cells of a human patient previously
infected with the virus.102 This antibody has the po-
tential to be used for postexposure prophylaxis and
treatment of MERS-CoV, but data for its efficacy in
human patients are lacking.
Severe acute respiratory syndrome
coronavirus
SARS-CoV was discovered in 2002 during an
outbreak of 300 cases of rapidly progressive pneu-
monia in the Guoduong Province of China.103 Be-
tween 2002 and mid-2004, a total of 8096 cases
of SARS were reported, with a case fatality rate of
9.6%.104 The animal reservoir for SARS is not
known, although both palm civets and bats have
been implicated.105 During epidemics, SARS
spread from person to person by respiratory drop-
lets, and to a lesser extent by airborne and fecal-
oral transmission.106 Because of increased
transmission by close physical proximity, SARS
was frequently contracted by health care workers
caring for hospitalized patients.
The pathogenesis of SARS is incompletely un-
derstood, but is likely related to both viral infection
and immunopathologic injury. The functional
receptors for SARS coronavirus are angiotensin
receptor enzyme 2 (ACE-2) and CD209L.107,108
Autopsy studies of patient who have died of
SARS show that the lung and intestinal tract are
the primary sites of infection.109 Lung histology
often shows diffuse alveolar damage with varying
degrees of organization.110 Downregulation of
ACE-2 caused by viral replication, which plays a
Acute Respiratory Distress Syndrome 5
protective role in acute lung injury, has been impli-
cated in the development of ARDS in patients with
SARS.111
Clinical manifestations of SARS are a mild pro-
drome of fever and myalgias lasting 3 to 7 days,
during which viral replication occurs. Respiratory
symptoms, usually cough followed by dyspnea
and hypoxemia, occur during the second week
of the illness. Clinical worsening occurs during a
time of decreasing viral load, and may be caused
by immunopathologic injury rather than direct
injury from the virus.112 Dyspnea may progress
to respiratory failure, ARDS, and need for mechan-
ical ventilation.113 The radiographic pattern of
SARS is nonspecific, but it most commonly pre-
sents as ill-defined airspace opacities or ground-
glass opacities, with progression to multifocal
airspace opacities in patients who develop
ARDS.114,115 The diagnosis of SARS is made
from the presence of symptoms along with radio-
graphic abnormalities or autopsy consistent with
pneumonia and/or ARDS, and detection of virus
by RT-PCR from 2 body-fluid samples, cell culture
from a single sample, or detection of viral anti-
bodies by enzyme-linked immunosorbent assay
and/or immunofluorescent assays.116
During the SARS pandemic approximately 20%
of hospitalized patients developed ARDS.117,118
The management of patients with SARS and
ARDS is primarily supportive with low-tidal-
volume ventilation and other rescue therapies as
indicated. Strict infection control measures should
be instituted, including the isolation of affected pa-
tients, and the rigorous use of masks, gloves, and
gowns by health care workers to prevent human-
to-human transmission. During 2003, the most
severely ill patients with SARS were treated with
high-dose ribavirin, corticosteroids, or both. How-
ever, most experts agree that these therapies were
of little or no benefit, and adverse effects of these
therapies were common.119,120 SARS-CoV has
been dormant since the end of the outbreak in
2004. Vaccine development has been ongoing,
but the best approach remains an area of
debate.121
Seasonal Viruses
Seasonal respiratory viruses are identified in 22%
to 36% of adults with community-acquired-
pneumonia who require ICU admission.5,12,122
Influenza and rhinoviruses (human rhinoviruses
[HRVs]) are the most frequently detected viruses,
but respiratory syncytial virus (RSV), coronavi-
ruses, parainfluenza virus (PIV), human metapneu-
movirus (hMPV), and adenovirus are also
commonly reported. Whether these viruses are
6 Shah & Wunderink

the sole cause of pneumonia or ARDS is contro- HRV infection.132,133 Further studies of antiviral
versial; however, bacteria are less commonly iden- therapy in patients with HRV and critical illness
tified than viruses even when invasive methods are needed.
such as bronchoscopy are routinely used to test
for the cause of pneumonia.5 Although the precise Respiratory Syncytial Virus
frequency of ARDS caused by seasonal respira-
RSV, an enveloped paramyxovirus, is an important
tory viruses is unknown, the overall frequency is
cause of lower respiratory tract infection in chil-
probably very low.
dren but can infect people at all ages. RSV sub-
types A and B are responsible for most human
Rhinovirus disease. RSV epidemics occur during the winter
months and overlap with seasonal influenza.134
HRV, a single-stranded RNA virus of the Picorna-
In adults, RSV causes a range of clinical syn-
viridae family, is the most common cause of upper
dromes, including upper respiratory tract infection,
respiratory tract infections in adults and chil-
bronchitis, respiratory failure, and ARDS.135 Adults
dren.123 HRV is also one of the most commonly
with underlying cardiopulmonary disease, immu-
identified viruses in adults admitted to hospital
nocompromised state, hematopoietic bone
and ICU with CAP. Whether rhinovirus is the sole
marrow transplant, and those more than 65 years
cause of pneumonia, an incidental finding, a risk
of age are at risk for severe infection.136,137 In
factor for bacterial or viral coinfection, or asymp-
one study of elderly and hospitalized adults with
tomatic carriage, is controversial.15 In adults with
RSV infection, 15% were admitted to the ICU,
radiographically proven CAP, rhinovirus is identi-
13% required mechanical ventilation, and 8%
fied more frequently in patients with CAP
died.138
compared with asymptomatic controls.14,124 HRV
Antiviral therapy with ribavirin, in combination
has been shown to trigger cytokine release in
with human intravenous immunoglobulin (IVIG) or
both the lower respiratory epithelium and blood,
corticosteroids, may be beneficial in immunocom-
suggesting a potential pathogenic link to both
promised adults with severe pneumonia caused
pneumonia and ARDS.125,126
by RSV.139 A small case series suggested that
Rhinovirus has been reported as a cause of
both oral and inhaled ribavirin may improve
ARDS most frequently in elderly and immunocom-
morbidity and mortality in hematopoietic cell
promised adults.127 Autopsy findings of 4 bone
transplant recipients.140,141 Nonrandomized
marrow transplant patients with suspected HRV
studies of adult lung transplant recipients with
pneumonia showed findings consistent with viral
RSV infection suggested that combination therapy
pneumonia, including acute and chronic interstitial
with corticosteroids and ribavirin is effective.142,143
pneumonitis and diffuse alveolar damage with hy-
Ribavirin should be used with caution in some pa-
aline membrane consistent with ARDS.128 Among
tient populations. The inhaled formulation of riba-
patients with pneumonia admitted to an ICU at a
virin can provoke bronchospasm. Both inhaled
single center in South Korea, 96.2% of patients
and oral ribavirin are potential teratogens that
with HRV pneumonia required mechanical ventila-
should be used with caution in pregnant patients,
tion, and 59.3% had diffuse abnormalities on CXR
and pregnant health care providers should avoid
suggestive of ARDS.129 In another retrospective
contact with patients receiving aerosolized
analysis of 80 hospitalized adults with HRV infec-
ribavirin.
tion, 27.4% of whom were immunocompromised,
50% had radiographic evidence of pneumonia
Parainfluenza Virus
and 11.3% required ICU admission.130 In these
cohorts, mortality related to HRV ranged from PIVs are single-stranded, enveloped RNA viruses
2.3% to 55.7% and was highest among patients of the Paramyxoviridae family. Three serotypes
with an underlying immunocompromised state. cause clinical disease: PIV 1 and 2 are seen pri-
There is no clear role for antiviral therapy in crit- marily in the fall and winter months, whereas
ically ill adults with HRV pneumonia. The capsid- PIV3 is seen in the spring and summer seasons.
binding anti-HRV agent pleconaril reduces the Although PIV infections are generally self-limited,
duration of uncomplicated HRV upper respiratory hospitalization, ICU admission, and ARDS can
infections by 1 day; however, the drug was not occur.12,144 Patients with underlying obstructive
approved for clinical use because of concern for lung disease and immunocompromised hosts
drug-drug interactions.131 Intranasal recombinant may be more susceptible. In a retrospective cohort
interferon alfa-2b is effective in preventing HRV study of 253 hematopoietic cell transplant patients
colds when used for postexposure prophylaxis with PIV infection, 24.1% developed pneumonia
but is not effective for treatment of established and the associated mortality was 35%.145
 Acute Respiratory Distress Syndrome 7

No antiviral agents have shown efficacy Adenovirus

against PIV. Use of inhaled, oral, or intravenous
The adenovirus is part of the nonenveloped family
ribavirin for the treatment of PIV has been
of viruses with a double-stranded DNA genome.
described in case reports.146 However, a retro-
The true incidence of adenovirus in adults is diffi-
spective study of hematopoietic cell transplant
cult to estimate because testing for this virus is
recipients with parainfluenza who received
not routinely done; in most series, adenovirus is
inhaled ribavirin combined with IVIG or cortico-
found in 1% of ICU patients.5,12,13 In addition to
steroids showed no benefit in terms of either viral
typical lower respiratory symptoms, adults with
shedding or mortality.145 DAS181, an investiga-
adenovirus pneumonia may also present with
tional sialidase fusion protein, has in vitro activity
abdominal complaints, such as diarrhea, and
against PIV but the efficacy of this drug in
neurologic manifestations, such as encephalitis
humans is not known.147,148
and seizures. Outbreaks of severe adenovirus
pneumonia have been reported in military re-
Human Metapneumovirus cruits,163 residents of long-term care facilities,164
and immunocompromised individuals.165,166
hMPV is an enveloped negative-sense RNA virus
Although rare, ARDS has been reported in immu-
of the Paramyxoviridae family, discovered in
nocompetent adults.167,168 Adenovirus can be
2001.149 hMPV infections show the seasonal vari-
detected by RT-PCR from an NP, lower respira-
ation typical of RSV and are usually mild and self-
tory, or stool sample, but the diagnosis should
limiting. hMPV is difficult to culture in vitro, and the
be confirmed by PCR or cell culture detection
diagnosis is more readily made using RT-PCR
from a sterile site such as blood, cerebrospinal
from an NP or lower respiratory tract specimen.150
fluid, or tissue biopsy.
Respiratory failure and ARDS caused by hMPV
In addition to supportive care, patients with se-
have been reported in adults, including residents
vere adenovirus pneumonia and ARDS may benefit
of long-term care facilities151,152 and severely
from antiviral therapy. Cidofovir, a mononucleotide
immunocompromised patients, such as those
analog of cytosine, reduces viral load and improves
with bone marrow transplant153 and acquired hu-
clinical symptoms in patients with hematopoietic
man deficiency syndrome.28 In a case series of
stem cell transplant and invasive adenoviral disease
128 hospitalized adults with hMPV infection,
compared with historical controls.169 In a case se-
31% required ICU admission and 14.8% devel-
ries of 7 immunocompetent adults with adenovirus
oped ARDS.154
pneumonia who were administered cidofovir within
Animal models show that hMPV infects bronchial
48 hours of diagnosis, all survived and had radio-
epithelial cells, leading to bronchial hyperrespon-
graphic resolution of pneumonia by 21 days.170
siveness, and induces proinflammatory cytokines,
Brincidofovir, a lipid-linked derivative of cidofovir,
including interleukin (IL)-2, IL-8, IL-4, and interferon
is currently under phase III clinical trials in hemato-
alfa.155,156 Histopathologic changes suggestive of
poietic stem cell transplant patients.171 Pooled hu-
ARDS, including hyaline membrane formation and
man IVIG has high levels of neutralizing antibodies
organizing pneumonia–like reaction, have been
against adenoviruses and can be used as adjunctive
described in open-lung or transbronchial biopsy
therapy.169 In a retrospective review, the use of cor-
specimens of immunocompromised patients with
ticosteroids in immunocompetent patients with
hMPV identified on BAL.157 Murine models have
adenovirus pneumonia did not show any benefit.172
also shown that hMPV increases the risk of severe
secondary pneumococcal infection similar to influ-
enza A virus.158 SUMMARY
Antiviral therapy for hMPV is not well estab-
lished, but several antiviral agents for severe Respiratory viruses are a common cause of se-
hMPV are under investigation. Ribavirin limits vere pneumonia and ARDS in adults. The advent
viral replication and downregulates cytokine pro- of new diagnostic technologies, particularly multi-
duction in in vivo and mouse modelsl159; howev- plex reaction-PCR, have increased the recogni-
er, uncontrolled case series of patients with tion of viral respiratory infections in critically ill
hMPV infection treated with ribavirin have not adults. Supportive care for adults with ARDS
shown a consistent improvement in out- caused by respiratory viruses is similar to the
comes.160,161 A monoclonal antibody against care of patients with ARDS from other causes.
the hMPV fusion protein seems to have both pro- Although antiviral therapy is available for some
phylactic and therapeutic benefit in mouse respiratory viral infections, further research is
models162 but studies in human subjects are needed to determine which groups of patients
currently lacking. would benefit.
8 Shah & Wunderink
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